Using kinetic isotope effects to determine

Using kinetic isotope effects to determine the structure of the transition states of SN2 reactions, 41, 219... 

A reaction described as Sn2, abbreviation for substitution, nucleophilic (bimolecular), is a one-step process, and no intermediate is formed. This reaction involves the so-called backside attack of a nucleophile Y on an electrophilic center RX, such that the reaction center the carbon or other atom attacked by the nucleophile) undergoes inversion of stereochemical configuration. In the transition-state nucleophile and exiphile (leaving group) reside at the reaction center. Aside from stereochemical issues, other evidence can be used to identify Sn2 reactions. First, because both nucleophile and substrate are involved in the rate-determining step, the reaction is second order overall rate = k[RX][Y]. Moreover, one can use kinetic isotope effects to distinguish SnI and Sn2 cases (See Kinetic Isotope Effects). 

Reports in the literature that isolate any of these processes are rare and often require unusual conditions. For example, in addition to the oxazoI-5(4//)-one studies described above, Kemp and Rebek[27l were able to use kinetic isotope effects to distinguish the enolization mechanism from oxazol-5(4//)-one formation in a simple peptide coupling experiment. a-2H-Labeled Bz-L-Leu-OH and Z-Gly-Phe-OH were prepared and coupling reactions to H-Gly-OEt were carried out. In cases where oxazol-5(4//)-one formation is rate-determining, such as with Bz- L-Leu-OH, the isotope effect kHlkD is equal to 1 because the a-proton is not removed until after this rate-determining step. In contrast, enolization requires the direct removal of the a-proton, and the isotope effect measured for this mechanism was as high as 2.9 with Z-Gly-Phe-OH. Therefore, a measurement of the isotope... 

Pham TV, Fang Y-R, Westaway KC (1997) Using secondary deuterium kinetic isotope effects to determine the symmetry of SN2 transition states. J. Am. Chem. Soc. 119 3670-3676... 

Kubisa and Penczek measured the ratio of secondary and tertiary oxonium ions in the polymerization of dioxolane by CF3SO3H and found that it varied with both the concentration of reagents and with conversion. The use of the kinetic isotope effect to determine the structure of active centres in the polymerization of heterocycles was described. " Bucquoye and Goethals discuss the mechan- D. J. Sikkema and H. AngadOaur, Makmmol. Chern-, 1980,181,22S9. 

Song and Beak161 have used intramolecular and intermolecular hydrogen-deuterium kinetic isotope effects to investigate the mechanism of the tin tetrachloride catalysed ene-carbonyl enophile addition reaction between diethyloxomalonate and methylenecy-clohexane (equation 105). These ene reactions with carbonyl enophiles can occur by a concerted (equation 106) or a stepwise mechanism (equation 107), where the formation of the intermediate is either fast and reversible and the second step is slow k- > k-i), or where the formation of the intermediate (the k step) is rate-determining. 

Rhee and Shine39 used an impressive combination of nitrogen and carbon kinetic isotope effects to demonstrate that a quinonoidal-type intermediate is formed in the rate-determining step of the acid-catalyzed disproportionation reaction of 4,4 -dichlorohydrazobenzene (equation 26). When the reaction was carried out at 0°C in 60% aqueous dioxane that was 0.5 M in perchloric acid and 0.5 M in lithium perchlorate, extensive product analyses indicated that the major pathway was the disproportionation reaction. In fact, the disproportionation reaction accounted for approximately 72% of the product (compounds 6 and 7) while approximately 13% went to the ortho-semidine (8) and approximately 15% was consumed in the para-semidine (9) rearrangement. 

Fig. 3 a Proposed mechanism of ODCase-catalyzed decarboxylation of OMP by 02 protonation. Both the protonation and decarboxylation steps would be expected to be slightly sensitive to isotopic substitution at Nl. b Model reactions used to assess the feasibility of the 02 protonation mechanism, or any mechanism with a pre-decarboxylation step that is isotopically sensitive at Nl, and the measured Nl equilibrium and kinetic isotope effects, a Data from [31]. b Data from [30]. c Model reactions for which Nl equilibrium and kinetic isotope effects were determined using computational approaches, and the computed values [32]... 

To investigate whether an enolate arylation was occurring, the authors prepared enantioenriched cyclopropane substrate 45 and submitted it to the reaction conditions (Scheme 11). After 3 h, all starting material was consumed, and spirooxindole product 46 showed little erosion of enantioselectivity. Furthermore, the kinetic isotope effect was determined via parallel reactions to be 3.9, identifying C-H cleavage as a rate-determining step. This observation is not consistent with an enolate-like pathway. Furthermore, the use of a weak base (K2CO3) makes the enolate pathway quite unlikely. 

We have used inter- and intramolecular kinetic isotope effects to examine the mechanism of these Lewis acid catalyzed ene reactions. The Lewis acid catalyzed ene reaction has traditionally been though to proceed through either a concerted pericyclic mechanism or a stepwise reaction with a zwitterionic intermediate. We found that the intermolecular isotope effect in the Me2AlQ catalyzed ene reaction of formaldehyde is 1.3 with methylenecyclohexane and methylenecyclohex-ane-2,2,6,6- 4 and 1.4 with 2,3-dimethyl-2-butene and 2,3-dimethyl-2-butene- /i2. Since secondary iotope effects could be responsible for these results, these values are consistent with either a stepwise or concerted mechanism. Intramolecular isotope effects were determined to be 2.9 and 2.7 with 2 and 3, respectively. These substantial intramolecular isotope effects coupled with the small intermolecular isotope effects indicate that the reaction is stepwise with proton transfer following the rate determining step. In an intramolecular competition such as the ene reactions of formaldehyde with 2 and 3 an isotope effect will still be observed if the hydrogen transfer occurs... 

A special type of substituent effect which has proved veiy valuable in the study of reaction mechanisms is the replacement of an atom by one of its isotopes. Isotopic substitution most often involves replacing protium by deuterium (or tritium) but is applicable to nuclei other than hydrogen. The quantitative differences are largest, however, for hydrogen, because its isotopes have the largest relative mass differences. Isotopic substitution usually has no effect on the qualitative chemical reactivity of the substrate, but often has an easily measured effect on the rate at which reaction occurs. Let us consider how this modification of the rate arises. Initially, the discussion will concern primary kinetic isotope effects, those in which a bond to the isotopically substituted atom is broken in the rate-determining step. We will use C—H bonds as the specific topic of discussion, but the same concepts apply for other elements. 

The exo and the endo ring closures (the kc reactions) are in competition with the aryl radical-tributyltin hydride transfer (the ks or ku reaction). These workers162 used this competition to determine the primary hydrogen-deuterium kinetic isotope effect in the hydride transfer reaction between the aryl radical and tributyltin hydride and deuteride. 

In one study, Ingold and coworkers166 measured the rate constants for the reactions of several alkyl radicals with tributyltin hydride using a laser flash photolytic technique and direct observation of the tributyltin radical. They also used this technique with tributyltin deuteride to determine the primary hydrogen-deuterium kinetic isotope effects for three of these reactions. The isotope effects were 1.9 for reaction of the ethyl radical, and 2.3 for reaction of the methyl and n -butyl radicals with tributyltin hydride at 300 K. 

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